ABSTRACT: Background and Objective: Previous research has speculated on the role of pro- and inflammatory immune mediators in the etiologic process of fatigue, with contrasting findings. The preponderance of the evidence supports the role of inflammatory mediators in the disease process of Chronic Fatigue Syndrome (CFS). The purpose of this study was to evaluate the production of interleukin (IL)-8 by peripheral blood mononuclear cells derived from individuals with chronic fatigue. A secondary objective was to determine if there was a significant relationship between IL-8 production and plasma cortisol level. Materials and Methodology: Data was collected from three groups, a sample of individuals with CFS (n = 15), a comparison sample of individuals with fatigue that did not meet criteria for CFS (n = 30) and a group of putatively health normative controls (n = 23). Peripheral blood was drawn and plasma samples derived. Peripheral blood mononuclear cells were stimulated with a mitogenic protocol and levels of IL8 in unstimulated and stimulated bulk supernatant determined. Results: Both fatigue groups displayed significantly higher levels of IL8 than the control group. The CFS group demonstrated higher levels of IL8 in plasma than the fatigue comparison group. Conclusion: The findings demonstrate a clear association between fatigue and IL8. The ability to identify an inflammatory marker in association with fatigue could provide a means of identifying those who may be at risk for the development of this disorder.